Transcription factors can be activated in various ways. One way that cells control their activity is by sequestering these proteins outside of the nucleus, denying them access to the promoters that they bind. In some cases, transcription factor activation involves cleavage to allow nuclear translocation. Andréasson et al. report that in Saccharomyces cerevisiae, receptor-activated proteolysis is the mechanism by which amino acid sensing leads to stimulation of amino acid uptake through the Ssy1-Ptr3-Ssy5 (SPS) pathway. Two cleavage events occur in the SPS pathway: autoproteolysis of Ssy5, a protein associated with the transmembrane amino acid receptor Ssy1, and stimulated cleavage of Stp1 and Stp2, the transcription factors activated in response to amino acids. Andréasson et al. show that Ssy5 interacts with Stp1 and that a fusion construct containing the region of Stp1 required for processing was cleaved when expressed in yeast exposed to leucine. Yeast deficient in Ssy5 did not cleave the Stp1 fusion construct. When an N terminally hemagglutinin-tagged form of Ssy5, which was constitutively active, was coexpressed with Stp1 in S. pombe, which lacks any orthologs of the SPS system, Stp1 was efficiently cleaved. Because tagging Ssy5 on the N terminus resulted in constitutive activation, the authors created a C terminally tagged form and found that the prodomain remained associated with the catalytic domain after cleavage. Using an internally tagged form of Ssy5, the activity of which was regulated by amino acids, the authors showed that the abundance of the prodomain diminished during a 30-minute exposure of the yeast to leucine. The authors suggest that Ssy5 autoproteolysis serves as a priming event and that upon detection of amino acids by Ssy1, an inhibitory interaction between the cleaved prodomain of Ssy5 and the catalytic domain of Ssy5 is alleviated, which allows Ssy5 to cleave Stp1, promoting nuclear translocation and transcriptional activation. They dub this mechanism of proteolytic activation "receptor-activated proteolysis" (RAP).